DNA repair gene polymorphisms and adult acute myeloblastic leukaemia risk

CH Seedhouse, PhD, E P Das-Gupta, MD, M Lewis and N H Russell, MD.

Deparmtent of Academic Haematology, Clinical Sciences Building, Nottingham City Hospital, Nottingham, NG5 1PB, United Kingdom

AIM DNA repair mechanisms play a vital role in maintaining genetic integrity. Recently, a number of polymorphisms in several DNA repair genes have been described, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility via gene-environment interactions. We are investigating DNA repair capacity and its potential association with acute myeloblastic leukaemia and myelodysplastic syndrome. We have chosen to study polymorphisms in two DNA repair genes. The XRCC1 gene product plays an important role in the base excision repair pathway by acting as a scaffold for other DNA repair proteins and by recognizing single strand breaks. Several variants of XRCC1 have been described including one affecting codon 399 in exon 10; Arg399Met. XRCC3 interacts with Rad51 and is believed to be a component of double strand break recombinational repair. XRCC3 Thr241Met is the second polymorphism we have studied in our patient cohort. METHODS We have genotyped the above polymorphisms by PCR-RFLP in 117 AML cases, 88 MDS cases and 92 healthy controls. RESULTS The distribution of the XRCC3-241 genotypes was not significantly different among patients and controls. However the distribution of the XRCC1-399 genotypes was significantly different when comparing the AML and control groups (chi-square, p = 0.01) although there was no significant difference when comparing the MDS and control groups. In contrary to some publications associating the polymorphic XRCC1-399Gln allele and several different forms of cancer, the XRCC1-399Gln allele does not indicate an association with adult AML, odds ratio = 0.62 (95% confidence intervals 0.36-1.10), however the odds ratio for the non-polymorphic XRCC1-399Arg allele is 1.621 (95% confidence interval 0.82-3.2). CONCLUSIONS Our data suggest that the inheritance of the XRCC1-399Arg allele might increase the risk of developing adult AML. We are currently studying polymorphisms in other DNA repair genes.

KEY WORDS: myelodysplastic syndrome.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.